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22 pages, 2846 KiB

Open AccessArticle

Muscle Proteomic and Transcriptomic Profiling of Healthy Aging and Metabolic Syndrome in Men

by Marine Gueugneau, Cécile Coudy-Gandilhon, Christophe Chambon, Julien Verney, Daniel Taillandier, Lydie Combaret, Cécile Polge, Stéphane Walrand, Frédéric Roche, Jean-Claude Barthélémy, Léonard Féasson and Daniel Béchet

Int. J. Mol. Sci. 2021, 22(8), 4205; https://doi.org/10.3390/ijms22084205 - 19 Apr 2021

Cited by 19 | Viewed by 4429

Abstract

(1) Background: Aging is associated with a progressive decline in muscle mass and function. Aging is also a primary risk factor for metabolic syndrome, which further alters muscle metabolism. However, the molecular mechanisms involved remain to be clarified. Herein we performed omic profiling [...] Read more.

(1) Background: Aging is associated with a progressive decline in muscle mass and function. Aging is also a primary risk factor for metabolic syndrome, which further alters muscle metabolism. However, the molecular mechanisms involved remain to be clarified. Herein we performed omic profiling to decipher in muscle which dominating processes are associated with healthy aging and metabolic syndrome in old men. (2) Methods: This study included 15 healthy young, 15 healthy old, and 9 old men with metabolic syndrome. Old men were selected from a well-characterized cohort, and each vastus lateralis biopsy was used to combine global transcriptomic and proteomic analyses. (3) Results: Over-representation analysis of differentially expressed genes (ORA) and functional class scoring of pathways (FCS) indicated that healthy aging was mainly associated with upregulations of apoptosis and immune function and downregulations of glycolysis and protein catabolism. ORA and FCS indicated that with metabolic syndrome the dominating biological processes were upregulation of proteolysis and downregulation of oxidative phosphorylation. Proteomic profiling matched 586 muscle proteins between individuals. The proteome of healthy aging revealed modifications consistent with a fast-to-slow transition and downregulation of glycolysis. These transitions were reduced with metabolic syndrome, which was more associated with alterations in NADH/NAD⁺ shuttle and β-oxidation. Proteomic profiling further showed that all old muscles overexpressed protein chaperones to preserve proteostasis and myofiber integrity. There was also evidence of aging-related increases in reactive oxygen species but better detoxifications of cytotoxic aldehydes and membrane protection in healthy than in metabolic syndrome muscles. (4) Conclusions: Most candidate proteins and mRNAs identified herein constitute putative muscle biomarkers of healthy aging and metabolic syndrome in old men. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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19 pages, 2781 KiB

Open AccessArticle

Role of Sphingosine 1-Phosphate Signalling Axis in Muscle Atrophy Induced by TNFα in C2C12 Myotubes

by Caterina Bernacchioni, Veronica Ghini, Roberta Squecco, Eglantina Idrizaj, Rachele Garella, Elisa Puliti, Francesca Cencetti, Paola Bruni and Chiara Donati

Int. J. Mol. Sci. 2021, 22(3), 1280; https://doi.org/10.3390/ijms22031280 - 28 Jan 2021

Cited by 15 | Viewed by 3262

Abstract

Skeletal muscle atrophy is characterized by a decrease in muscle mass causing reduced agility, increased fatigability and higher risk of bone fractures. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), are strong inducers of skeletal muscle atrophy. The bioactive sphingolipid sphingosine 1-phoshate (S1P) [...] Read more.

Skeletal muscle atrophy is characterized by a decrease in muscle mass causing reduced agility, increased fatigability and higher risk of bone fractures. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNFα), are strong inducers of skeletal muscle atrophy. The bioactive sphingolipid sphingosine 1-phoshate (S1P) plays an important role in skeletal muscle biology. S1P, generated by the phosphorylation of sphingosine catalyzed by sphingosine kinase (SK1/2), exerts most of its actions through its specific receptors, S1P_1–5. Here, we provide experimental evidence that TNFα induces atrophy and autophagy in skeletal muscle C2C12 myotubes, modulating the expression of specific markers and both active and passive membrane electrophysiological properties. NMR-metabolomics provided a clear picture of the deep remodelling of skeletal muscle fibre metabolism induced by TNFα challenge. The cytokine is responsible for the modulation of S1P signalling axis, upregulating mRNA levels of S1P₂ and S1P₃ and downregulating those of SK2. TNFα increases the phosphorylated form of SK1, readout of its activation. Interestingly, pharmacological inhibition of SK1 and specific antagonism of S1P₃ prevented the increase in autophagy markers and the changes in the electrophysiological properties of C2C12 myotubes without affecting metabolic remodelling induced by the cytokine, highlighting the involvement of S1P signalling axis on TNFα-induced atrophy in skeletal muscle. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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20 pages, 2588 KiB

Open AccessArticle

Can Serum Nitrosoproteome Predict Longevity of Aged Women?

by Daniele Capitanio, Pietro Barbacini, Beatrice Arosio, Franca Rosa Guerini, Enrica Torretta, Fabio Trecate, Matteo Cesari, Daniela Mari, Mario Clerici and Cecilia Gelfi

Int. J. Mol. Sci. 2020, 21(23), 9009; https://doi.org/10.3390/ijms21239009 - 27 Nov 2020

Cited by 6 | Viewed by 2524

Abstract

Aging is characterized by increase in reactive oxygen (ROS) and nitrogen (RNS) species, key factors of cardiac failure and disuse-induced muscle atrophy. This study focused on serum nitroproteome as a trait of longevity by adopting two complementary gel-based techniques: two-dimensional differential in gel [...] Read more.

Aging is characterized by increase in reactive oxygen (ROS) and nitrogen (RNS) species, key factors of cardiac failure and disuse-induced muscle atrophy. This study focused on serum nitroproteome as a trait of longevity by adopting two complementary gel-based techniques: two-dimensional differential in gel electrophoresis (2-D DIGE) and Nitro-DIGE coupled with mass spectrometry of albumin-depleted serum of aged (A, n = 15) and centenarian (C, n = 15) versus young females (Y, n = 15). Results indicate spots differently expressed in A and C compared to Y and spots changed in A vs. C. Nitro-DIGE revealed nitrosated protein spots in A and C compared to Y and spots changed in A vs. C only (p-value < 0.01). Nitro-proteoforms of alpha-1-antitripsin (SERPINA1), alpha-1-antichimotripsin (SERPINA3), ceruloplasmin (CP), 13 proteoforms of haptoglobin (HP), and inactive glycosyltransferase 25 family member 3 (CERCAM) increased in A vs. Y and C. Conversely, nitrosation levels decreased in C vs. Y and A, for immunoglobulin light chain 1 (IGLC1), serotransferrin (TF), transthyretin (TTR), and vitamin D-binding protein (VDBP). Immunoblottings of alcohol dehydrogenase 5/S-nitrosoglutathione reductase (ADH5/GSNOR) and thioredoxin reductase 1 (TRXR1) indicated lower levels of ADH5 in A vs. Y and C, whereas TRXR1 decreased in A and C in comparison to Y. In conclusion, the study identified putative markers in C of healthy aging and high levels of ADH5/GSNOR that can sustain the denitrosylase activity, promoting longevity. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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19 pages, 20961 KiB

Open AccessArticle

Emerging Role for Linear and Circular Spermine Oxidase RNAs in Skeletal Muscle Physiopathology

by Jonathan Fernando Reinoso-Sánchez, Giulia Baroli, Guglielmo Duranti, Silvia Scaricamazza, Stefania Sabatini, Cristiana Valle, Mariangela Morlando, Robert Anthony Casero, Jr., Irene Bozzoni, Paolo Mariottini, Roberta Ceci and Manuela Cervelli

Int. J. Mol. Sci. 2020, 21(21), 8227; https://doi.org/10.3390/ijms21218227 - 3 Nov 2020

Cited by 12 | Viewed by 3174

Abstract

Skeletal muscle atrophy is a pathological condition so far without effective treatment and poorly understood at a molecular level. Emerging evidence suggest a key role for circular RNAs (circRNA) during myogenesis and their deregulation has been reported to be associated with muscle diseases. [...] Read more.

Skeletal muscle atrophy is a pathological condition so far without effective treatment and poorly understood at a molecular level. Emerging evidence suggest a key role for circular RNAs (circRNA) during myogenesis and their deregulation has been reported to be associated with muscle diseases. Spermine oxidase (SMOX), a polyamine catabolic enzyme plays a critical role in muscle differentiation and the existence of a circRNA arising from SMOX gene has been recently identified. In this study, we evaluated the expression profile of circular and linear SMOX in both C2C12 differentiation and dexamethasone-induced myotubes atrophy. To validate our findings in vivo their expression levels were also tested in two murine models of amyotrophic lateral sclerosis: SOD1^G93A and hFUS^+/+, characterized by progressive muscle atrophy. During C2C12 differentiation, linear and circular SMOX show the same trend of expression. Interestingly, in atrophy circSMOX levels significantly increased compared to the physiological state, in both in vitro and in vivo models. Our study demonstrates that SMOX represents a new player in muscle physiopathology and provides a scientific basis for further investigation on circSMOX RNA as a possible new therapeutic target for the treatment of muscle atrophy. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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30 pages, 29399 KiB

Open AccessArticle

Prolonged Immobilization Exacerbates the Loss of Muscle Mass and Function Induced by Cancer-Associated Cachexia through Enhanced Proteolysis in Mice

by Laura Mañas-García, Antonio Penedo-Vázquez, Adrián López-Postigo, Jorieke Deschrevel, Xavier Durán and Esther Barreiro

Int. J. Mol. Sci. 2020, 21(21), 8167; https://doi.org/10.3390/ijms21218167 - 31 Oct 2020

Cited by 9 | Viewed by 3497

Abstract

We hypothesized that in mice with lung cancer (LC)-induced cachexia, periods of immobilization of the hindlimb (7 and 15 days) may further aggravate the process of muscle mass loss and function. Mice were divided into seven groups (n = 10/group): (1) non-immobilized [...] Read more.

We hypothesized that in mice with lung cancer (LC)-induced cachexia, periods of immobilization of the hindlimb (7 and 15 days) may further aggravate the process of muscle mass loss and function. Mice were divided into seven groups (n = 10/group): (1) non-immobilized control mice, (2) 7-day unloaded mice (7-day I), (3) 15-day unloaded mice (15-day I), (4) 21-day LC-cachexia group (LC 21-days), (5) 30-day LC-cachexia group (LC 30-days), (6) 21-day LC-cachexia group besides 7 days of unloading (LC 21-days + 7-day I), (7) 30-day LC-cachexia group besides 15 days of unloading (LC 30-days + 15-day I). Physiological parameters, body weight, muscle and tumor weights, phenotype and morphometry, muscle damage (including troponin I), proteolytic and autophagy markers, and muscle regeneration markers were identified in gastrocnemius muscle. In LC-induced cachexia mice exposed to hindlimb unloading, gastrocnemius weight, limb strength, fast-twitch myofiber cross-sectional area, and muscle regeneration markers significantly decreased, while tumor weight and area, muscle damage (troponin), and proteolytic and autophagy markers increased. In gastrocnemius of cancer-cachectic mice exposed to unloading, severe muscle atrophy and impaired function was observed along with increased muscle proteolysis and autophagy, muscle damage, and impaired muscle regeneration. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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23 pages, 3234 KiB

Open AccessArticle

Sarcopenia Induced by Chronic Liver Disease in Mice Requires the Expression of the Bile Acids Membrane Receptor TGR5

by Johanna Abrigo, Fabián Campos, Francisco Gonzalez, Francisco Aguirre, Andrea Gonzalez, Camila Huerta-Salgado, Sabrina Conejeros, Felipe Simon, Marco Arrese, Daniel Cabrera, Alvaro A. Elorza and Claudio Cabello-Verrugio

Int. J. Mol. Sci. 2020, 21(21), 7922; https://doi.org/10.3390/ijms21217922 - 25 Oct 2020

Cited by 18 | Viewed by 4775

Abstract

Sarcopenia is a condition of muscle dysfunction, commonly associated with chronic liver disease (CLD), characterized by a decline in muscle strength, the activation of the ubiquitin-proteasome system (UPS), and oxidative stress. We recently described a murine model of CLD-induced sarcopenia by intake of [...] Read more.

Sarcopenia is a condition of muscle dysfunction, commonly associated with chronic liver disease (CLD), characterized by a decline in muscle strength, the activation of the ubiquitin-proteasome system (UPS), and oxidative stress. We recently described a murine model of CLD-induced sarcopenia by intake of hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which presents an increase in plasma bile acids (BA). BA induced skeletal muscle atrophy through a mechanism dependent on the Takeda G protein-coupled receptor 5 (TGR5) receptor. In the present study, we evaluated the role of TGR5 signaling in the development of sarcopenia using a model of DDC-induced CLD in C57BL6 wild-type (WT) mice and mice deficient in TGR5 expression (TGR5^−/− mice). The results indicate that the decline in muscle function and contractibility induced by the DDC diet is dependent on TGR5 expression. TGR5 dependence was also observed for the decrease in fiber diameter and sarcomeric proteins, as well as for the fast-to-slow shift in muscle fiber type. UPS overactivation, indicated by increased atrogin-1/MAFbx (atrogin-1) and muscle RING-finger protein-1 (MuRF-1) protein levels and oxidative stress, was abolished in tibialis anterior muscles from TGR5^−/− mice. Our results collectively suggest that all sarcopenia features induced by the DDC-supplemented diet in mice are dependent on TGR5 receptor expression. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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13 pages, 1929 KiB

Open AccessArticle

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

by Megan E. Rosa-Caldwell, Conner A. Benson, David E. Lee, Jacob L. Brown, Tyrone A. Washington, Nicholas P. Greene and Michael P. Wiggs

Int. J. Mol. Sci. 2020, 21(21), 7841; https://doi.org/10.3390/ijms21217841 - 22 Oct 2020

Cited by 9 | Viewed by 3088

Abstract

It is established that cancer cachexia causes limb muscle atrophy and is strongly associated with morbidity and mortality; less is known about how the development of cachexia impacts the diaphragm. The purpose of this study was to investigate cellular signaling mechanisms related to [...] Read more.

It is established that cancer cachexia causes limb muscle atrophy and is strongly associated with morbidity and mortality; less is known about how the development of cachexia impacts the diaphragm. The purpose of this study was to investigate cellular signaling mechanisms related to mitochondrial function, reactive oxygen species (ROS) production, and protein synthesis during the development of cancer cachexia. C57BL/J6 mice developed Lewis Lung Carcinoma for either 0 weeks (Control), 1 week, 2 weeks, 3 weeks, or 4 weeks. At designated time points, diaphragms were harvested and analyzed. Mitochondrial respiratory control ratio was ~50% lower in experimental groups, which was significant by 2 weeks of cancer development, with no difference in mitochondrial content markers COXIV or VDAC. Compared to the controls, ROS was 4-fold elevated in 2-week animals but then was not different at later time points. Only one antioxidant protein, GPX3, was altered by cancer development (~70% lower in experimental groups). Protein synthesis, measured by a fractional synthesis rate, appeared to become progressively lower with the cancer duration, but the mean difference was not significant. The development and progression of cancer cachexia induces marked alterations to mitochondrial function and ROS production in the diaphragm and may contribute to increased cachexia-associated morbidity and mortality. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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17 pages, 2400 KiB

Open AccessArticle

MBNL1-Associated Mitochondrial Dysfunction and Apoptosis in C2C12 Myotubes and Mouse Skeletal Muscle

by Shingo Yokoyama, Yoshitaka Ohno, Tatsuro Egawa, Kazuya Ohashi, Rika Ito, Huascar Pedro Ortuste Quiroga, Tomohiro Yamashita and Katsumasa Goto

Int. J. Mol. Sci. 2020, 21(17), 6376; https://doi.org/10.3390/ijms21176376 - 2 Sep 2020

Cited by 7 | Viewed by 4154

Abstract

We explored the interrelationship between a tissue-specific alternative splicing factor muscleblind-like 1 (MBNL1) and peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), B-cell lymphoma 2 (Bcl-2) or Bcl-2-associated X protein (Bax) in C2C12 myotubes and mouse skeletal muscle to investigate a possible physiological role of [...] Read more.

We explored the interrelationship between a tissue-specific alternative splicing factor muscleblind-like 1 (MBNL1) and peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α), B-cell lymphoma 2 (Bcl-2) or Bcl-2-associated X protein (Bax) in C2C12 myotubes and mouse skeletal muscle to investigate a possible physiological role of MBNL1 in mitochondrial-associated apoptosis of skeletal muscle. Expression level of PGC-1α and mitochondrial membrane potential evaluated by the fluorescence ratio of JC-1 aggregate to monomer in C2C12 myotubes were suppressed by knockdown of MBNL1. Conversely, the ratio of Bax to Bcl-2 as well as the apoptotic index in C2C12 myotubes was increased by MBNL1 knockdown. In plantaris muscle, on the other hand, not only the minimum muscle fiber diameter but also the expression level of MBNL1 and PGC-1α in of 100-week-old mice were significantly lower than that of 10-week-old mice. Furthermore, the ratio of Bax to Bcl-2 in mouse plantaris muscle was increased by aging. These results suggest that MBNL1 may play a key role in aging-associated muscle atrophy accompanied with mitochondrial dysfunction and apoptosis via mediating PGC-1α expression in skeletal muscle. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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28 pages, 3424 KiB

Open AccessArticle

Transcriptional Changes Involved in Atrophying Muscles during Prolonged Fasting in Rats

by Marianne Ibrahim, Thierry Wasselin, Etienne Challet, Alain Van Dorsselaer, Yvon Le Maho, Thierry Raclot and Fabrice Bertile

Int. J. Mol. Sci. 2020, 21(17), 5984; https://doi.org/10.3390/ijms21175984 - 20 Aug 2020

Cited by 8 | Viewed by 3456

Abstract

Food deprivation resulting in muscle atrophy may be detrimental to health. To better understand how muscle mass is regulated during such a nutritional challenge, the current study deciphered muscle responses during phase 2 (P2, protein sparing) and phase 3 (P3, protein mobilization) of [...] Read more.

Food deprivation resulting in muscle atrophy may be detrimental to health. To better understand how muscle mass is regulated during such a nutritional challenge, the current study deciphered muscle responses during phase 2 (P2, protein sparing) and phase 3 (P3, protein mobilization) of prolonged fasting in rats. This was done using transcriptomics analysis and a series of biochemistry measurements. The main findings highlight changes for plasma catabolic and anabolic stimuli, as well as for muscle transcriptome, energy metabolism, and oxidative stress. Changes were generally consistent with the intense use of lipids as fuels during P2. They also reflected increased muscle protein degradation and repressed synthesis, in a more marked manner during P3 than P2 compared to the fed state. Nevertheless, several unexpected changes appeared to be in favor of muscle protein synthesis during fasting, notably at the level of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, transcription and translation processes, and the response to oxidative stress. Such mechanisms might promote protein sparing during P2 and prepare the restoration of the protein compartment during P3 in anticipation of food intake for optimizing the effects of an upcoming refeeding, thereby promoting body maintenance and survival. Future studies should examine relevance of such targets for improving nitrogen balance during catabolic diseases. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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18 pages, 3056 KiB

Open AccessArticle

Membrane Repair Deficit in Facioscapulohumeral Muscular Dystrophy

by Adam J. Bittel, Sen Chandra Sreetama, Daniel C. Bittel, Adam Horn, James S. Novak, Toshifumi Yokota, Aiping Zhang, Rika Maruyama, Kenji Rowel Q. Lim, Jyoti K. Jaiswal and Yi-Wen Chen

Int. J. Mol. Sci. 2020, 21(15), 5575; https://doi.org/10.3390/ijms21155575 - 4 Aug 2020

Cited by 16 | Viewed by 5024

Abstract

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. [...] Read more.

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD (FLExDUX4) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4-targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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17 pages, 2548 KiB

Open AccessArticle

Molecular Mechanisms of Muscle Weakness Associated with E173A Mutation in Tpm3.12. Troponin Ca²⁺ Sensitivity Inhibitor W7 Can Reduce the Damaging Effect of This Mutation

by Yurii S. Borovikov, Armen O. Simonyan, Stanislava V. Avrova, Vladimir V. Sirenko, Charles S. Redwood and Olga E. Karpicheva

Int. J. Mol. Sci. 2020, 21(12), 4421; https://doi.org/10.3390/ijms21124421 - 22 Jun 2020

Cited by 5 | Viewed by 2441

Abstract

Substitution of Ala for Glu residue in position 173 of γ-tropomyosin (Tpm3.12) is associated with muscle weakness. Here we observe that this mutation increases myofilament Ca²⁺-sensitivity and inhibits in vitro actin-activated ATPase activity of myosin subfragment-1 at high Ca²⁺. [...] Read more.

Substitution of Ala for Glu residue in position 173 of γ-tropomyosin (Tpm3.12) is associated with muscle weakness. Here we observe that this mutation increases myofilament Ca²⁺-sensitivity and inhibits in vitro actin-activated ATPase activity of myosin subfragment-1 at high Ca²⁺. In order to determine the critical conformational changes in myosin, actin and tropomyosin caused by the mutation, we used the technique of polarized fluorimetry. It was found that this mutation changes the spatial arrangement of actin monomers and myosin heads, and the position of the mutant tropomyosin on the thin filaments in muscle fibres at various mimicked stages of the ATPase cycle. At low Ca²⁺ the E173A mutant tropomyosin shifts towards the inner domains of actin at all stages of the cycle, and this is accompanied by an increase in the number of switched-on actin monomers and myosin heads strongly bound to F-actin even at relaxation. Contrarily, at high Ca²⁺ the amount of the strongly bound myosin heads slightly decreases. These changes in the balance of the strongly bound myosin heads in the ATPase cycle may underlie the occurrence of muscle weakness. W7, an inhibitor of troponin Ca²⁺-sensitivity, restores the increase in the number of myosin heads strongly bound to F-actin at high Ca²⁺ and stops their strong binding at relaxation, suggesting the possibility of using Ca²⁺-desensitizers to reduce the damaging effect of the E173A mutation on muscle fibre contractility. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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12 pages, 6683 KiB

Open AccessArticle

Age Dependent Modification of the Metabolic Profile of the Tibialis Anterior Muscle Fibers in C57BL/6J Mice

by Emiliana Giacomello, Emanuela Crea, Lucio Torelli, Alberta Bergamo, Carlo Reggiani, Gianni Sava and Luana Toniolo

Int. J. Mol. Sci. 2020, 21(11), 3923; https://doi.org/10.3390/ijms21113923 - 30 May 2020

Cited by 24 | Viewed by 4929

Abstract

Skeletal muscle aging is accompanied by mass reduction and functional decline, as a result of multiple factors, such as protein expression, morphology of organelles, metabolic equilibria, and neural communication. Skeletal muscles are formed by multiple fibers that express different Myosin Heavy Chains (MyHCs) [...] Read more.

Skeletal muscle aging is accompanied by mass reduction and functional decline, as a result of multiple factors, such as protein expression, morphology of organelles, metabolic equilibria, and neural communication. Skeletal muscles are formed by multiple fibers that express different Myosin Heavy Chains (MyHCs) and have different metabolic properties and different blood supply, with the purpose to adapt their contraction to the functional need. The fine interplay between the different fibers composing a muscle and its architectural organization determine its functional properties. Immunohistochemical and histochemical analyses of the skeletal muscle tissue, besides evidencing morphological characteristics, allow for the precise determination of protein expression and metabolic properties, providing essential information at the single-fiber level. Aiming to gain further knowledge on the influence of aging on skeletal muscles, we investigated the expression of the MyHCs, the Succinate Dehydrogenase (SDH) activity, and the presence of capillaries and Tubular Aggregates (TAs) in the tibialis anterior muscles of physiologically aging C57BL/6J mice aged 8 (adult), 18 (middle aged), and 24 months (old). We observed an increase of type-IIB fast-contracting fibers, an increase of the oxidative capacity of type-IIX and -IIA fibers, a general decrease of the capillarization, and the onset of TAs in type-IIB fibers. These data suggest that aging entails a selective modification of the muscle fiber profiles. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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18 pages, 2259 KiB

Open AccessArticle

Mitophagy and Mitochondria Biogenesis Are Differentially Induced in Rat Skeletal Muscles during Immobilization and/or Remobilization

by Christiane Deval, Julie Calonne, Cécile Coudy-Gandilhon, Emilie Vazeille, Daniel Bechet, Cécile Polge, Daniel Taillandier, Didier Attaix and Lydie Combaret

Int. J. Mol. Sci. 2020, 21(10), 3691; https://doi.org/10.3390/ijms21103691 - 23 May 2020

Cited by 15 | Viewed by 3605

Abstract

Mitochondria alterations are a classical feature of muscle immobilization, and autophagy is required for the elimination of deficient mitochondria (mitophagy) and the maintenance of muscle mass. We focused on the regulation of mitochondrial quality control during immobilization and remobilization in rat gastrocnemius (GA) [...] Read more.

Mitochondria alterations are a classical feature of muscle immobilization, and autophagy is required for the elimination of deficient mitochondria (mitophagy) and the maintenance of muscle mass. We focused on the regulation of mitochondrial quality control during immobilization and remobilization in rat gastrocnemius (GA) and tibialis anterior (TA) muscles, which have very different atrophy and recovery kinetics. We studied mitochondrial biogenesis, dynamic, movement along microtubules, and addressing to autophagy. Our data indicated that mitochondria quality control adapted differently to immobilization and remobilization in GA and TA muscles. Data showed i) a disruption of mitochondria dynamic that occurred earlier in the immobilized TA, ii) an overriding role of mitophagy that involved Parkin-dependent and/or independent processes during immobilization in the GA and during remobilization in the TA, and iii) increased mitochondria biogenesis during remobilization in both muscles. This strongly emphasized the need to consider several muscle groups to study the mechanisms involved in muscle atrophy and their ability to recover, in order to provide broad and/or specific clues for the development of strategies to maintain muscle mass and improve the health and quality of life of patients. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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13 pages, 2701 KiB

Open AccessArticle

P38α-MAPK Signaling Inhibition Attenuates Soleus Atrophy during Early Stages of Muscle Unloading

by Svetlana P. Belova, Ekaterina P. Mochalova, Tatiana Y. Kostrominova, Boris S. Shenkman and Tatiana L. Nemirovskaya

Int. J. Mol. Sci. 2020, 21(8), 2756; https://doi.org/10.3390/ijms21082756 - 15 Apr 2020

Cited by 12 | Viewed by 3353

Abstract

To test the hypothesis that p38α-MAPK plays a critical role in the regulation of E3 ligase expression and skeletal muscle atrophy during unloading, we used VX-745, a selective p38α inhibitor. Three groups of rats were used: non-treated control (C), 3 days of unloading/hindlimb [...] Read more.

To test the hypothesis that p38α-MAPK plays a critical role in the regulation of E3 ligase expression and skeletal muscle atrophy during unloading, we used VX-745, a selective p38α inhibitor. Three groups of rats were used: non-treated control (C), 3 days of unloading/hindlimb suspension (HS), and 3 days HS with VX-745 inhibitor (HSVX; 10 mg/kg/day). Total weight of soleus muscle in HS group was reduced compared to C (72.3 ± 2.5 vs 83.0 ± 3 mg, respectively), whereas muscle weight in the HSVX group was maintained (84.2 ± 5 mg). The expression of muscle RING-finger protein-1 (MuRF1) mRNA was significantly increased in the HS group (165%), but not in the HSVX group (127%), when compared with the C group. The expression of muscle-specific E3 ubiquitin ligases muscle atrophy F-box (MAFbx) mRNA was increased in both HS and HSVX groups (294% and 271%, respectively) when compared with C group. The expression of ubiquitin mRNA was significantly higher in the HS (423%) than in the C and HSVX (200%) groups. VX-745 treatment blocked unloading-induced upregulation of calpain-1 mRNA expression (HS: 120%; HSVX: 107%). These results indicate that p38α-MAPK signaling regulates MuRF1 but not MAFbx E3 ligase expression and inhibits skeletal muscle atrophy during early stages of unloading. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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18 pages, 2987 KiB

Open AccessArticle

Expression Levels of Long Non-Coding RNAs Change in Models of Altered Muscle Activity and Muscle Mass

by Keisuke Hitachi, Masashi Nakatani, Shiori Funasaki, Ikumi Hijikata, Mizuki Maekawa, Masahiko Honda and Kunihiro Tsuchida

Int. J. Mol. Sci. 2020, 21(5), 1628; https://doi.org/10.3390/ijms21051628 - 27 Feb 2020

Cited by 24 | Viewed by 4422

Abstract

Skeletal muscle is a highly plastic organ that is necessary for homeostasis and health of the human body. The size of skeletal muscle changes in response to intrinsic and extrinsic stimuli. Although protein-coding RNAs including myostatin, NF-κβ, and insulin-like growth factor-1 (IGF-1), have [...] Read more.

Skeletal muscle is a highly plastic organ that is necessary for homeostasis and health of the human body. The size of skeletal muscle changes in response to intrinsic and extrinsic stimuli. Although protein-coding RNAs including myostatin, NF-κβ, and insulin-like growth factor-1 (IGF-1), have pivotal roles in determining the skeletal muscle mass, the role of long non-coding RNAs (lncRNAs) in the regulation of skeletal muscle mass remains to be elucidated. Here, we performed expression profiling of nine skeletal muscle differentiation-related lncRNAs (DRR, DUM1, linc-MD1, linc-YY1, LncMyod, Neat1, Myoparr, Malat1, and SRA) and three genomic imprinting-related lncRNAs (Gtl2, H19, and IG-DMR) in mouse skeletal muscle. The expression levels of these lncRNAs were examined by quantitative RT-PCR in six skeletal muscle atrophy models (denervation, casting, tail suspension, dexamethasone-administration, cancer cachexia, and fasting) and two skeletal muscle hypertrophy models (mechanical overload and deficiency of the myostatin gene). Cluster analyses of these lncRNA expression levels were successfully used to categorize the muscle atrophy models into two sub-groups. In addition, the expression of Gtl2, IG-DMR, and DUM1 was altered along with changes in the skeletal muscle size. The overview of the expression levels of lncRNAs in multiple muscle atrophy and hypertrophy models provides a novel insight into the role of lncRNAs in determining the skeletal muscle mass. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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12 pages, 2794 KiB

Open AccessArticle

Corylifol A from Psoralea corylifolia L. Enhances Myogenesis and Alleviates Muscle Atrophy

by Yeongeun Han, Hyejin Lee, Hua Li and Jae-Ha Ryu

Int. J. Mol. Sci. 2020, 21(5), 1571; https://doi.org/10.3390/ijms21051571 - 25 Feb 2020

Cited by 23 | Viewed by 5859

Abstract

Inflammatory conditions caused by cancer, chronic diseases or aging can lead to skeletal muscle atrophy. We identified myogenic compounds from Psoralea corylifolia (PC), a medicinal plant that has been used for the treatment of inflammatory and skin diseases. C2C12 mouse skeletal myoblasts were [...] Read more.

Inflammatory conditions caused by cancer, chronic diseases or aging can lead to skeletal muscle atrophy. We identified myogenic compounds from Psoralea corylifolia (PC), a medicinal plant that has been used for the treatment of inflammatory and skin diseases. C2C12 mouse skeletal myoblasts were differentiated in the presence of eight compounds isolated from PC to evaluate their myogenic potential. Among them, corylifol A showed the strongest transactivation of MyoD and increased expression of myogenic markers, such as MyoD, myogenin and myosin heavy chain (MHC). Corylifol A increased the number of multinucleated and MHC-expressing myotubes. We also found that the p38 MAPK signaling pathway is essential for the myogenic action of corylifol A. Atrophic condition was induced by treatment with dexamethasone. Corylifol A protected against dexamethasone-induced myotube loss by increasing the proportion of multinucleated MHC-expressing myotubes compared with dexamethasone-damaged myotubes. Corylifol A reduced the expression of muscle-specific ubiquitin-E3 ligases (MAFbx and MuRF1) and myostatin, while activating Akt. These dual effects of corylifol A, inhibition of catabolic and activation of anabolic pathways, protect myotubes against dexamethasone damage. In summary, corylifol A isolated from P. corylifolia alleviates muscle atrophic condition through activating myoblast differentiation and suppressing muscle degradation in atrophic conditions. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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Review

Jump to: Research

18 pages, 3024 KiB

Open AccessReview

Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

by Yann S. Gallot and Kyle R. Bohnert

Int. J. Mol. Sci. 2021, 22(5), 2567; https://doi.org/10.3390/ijms22052567 - 4 Mar 2021

Cited by 30 | Viewed by 5830

Abstract

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic [...] Read more.

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca²⁺) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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9 pages, 1021 KiB

Open AccessReview

The Role of Bone in Muscle Wasting

by Gordon L. Klein

Int. J. Mol. Sci. 2021, 22(1), 392; https://doi.org/10.3390/ijms22010392 - 31 Dec 2020

Cited by 1 | Viewed by 2633

Abstract

This review describes the role of bone resorption in muscle atrophy as well as in muscle protein anabolism. Both catabolic and anabolic pathways involve components of the proinflammatory cytokine families and release of factors stored in bone during resorption. The juxtaposition of the [...] Read more.

This review describes the role of bone resorption in muscle atrophy as well as in muscle protein anabolism. Both catabolic and anabolic pathways involve components of the proinflammatory cytokine families and release of factors stored in bone during resorption. The juxtaposition of the catabolic and anabolic resorption-dependent pathways raises new questions about control of release of factors from bone, quantity of release in a variety of conditions, and relation of factors released from bone. The catabolic responses involve release of calcium from bone into the circulation resulting in increased inflammatory response in intensity and/or duration. The release of transforming growth factor beta (TGF-β) from bone suppresses phosphorylation of the AKT/mTOR pathway and stimulates ubiquitin-mediated breakdown of muscle protein. In contrast, muscle IL-6 production is stimulated by undercarboxylated osteocalcin, which signals osteoblasts to produce more RANK ligand, stimulating resorptive release of undercarboxylated osteocalcin, which in turn stimulates muscle fiber nutrient uptake and an increase in muscle mass. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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22 pages, 875 KiB

Open AccessReview

A Role for Caveolin-3 in the Pathogenesis of Muscular Dystrophies

by Bhola Shankar Pradhan and Tomasz J. Prószyński

Int. J. Mol. Sci. 2020, 21(22), 8736; https://doi.org/10.3390/ijms21228736 - 19 Nov 2020

Cited by 37 | Viewed by 8530

Abstract

Caveolae are the cholesterol-rich small invaginations of the plasma membrane present in many cell types including adipocytes, endothelial cells, epithelial cells, fibroblasts, smooth muscles, skeletal muscles and cardiac muscles. They serve as specialized platforms for many signaling molecules and regulate important cellular processes [...] Read more.

Caveolae are the cholesterol-rich small invaginations of the plasma membrane present in many cell types including adipocytes, endothelial cells, epithelial cells, fibroblasts, smooth muscles, skeletal muscles and cardiac muscles. They serve as specialized platforms for many signaling molecules and regulate important cellular processes like energy metabolism, lipid metabolism, mitochondria homeostasis, and mechano-transduction. Caveolae can be internalized together with associated cargo. The caveolae-dependent endocytic pathway plays a role in the withdrawal of many plasma membrane components that can be sent for degradation or recycled back to the cell surface. Caveolae are formed by oligomerization of caveolin proteins. Caveolin-3 is a muscle-specific isoform, whose malfunction is associated with several diseases including diabetes, cancer, atherosclerosis, and cardiovascular diseases. Mutations in Caveolin-3 are known to cause muscular dystrophies that are collectively called caveolinopathies. Altered expression of Caveolin-3 is also observed in Duchenne’s muscular dystrophy, which is likely a part of the pathological process leading to muscle weakness. This review summarizes the major functions of Caveolin-3 in skeletal muscles and discusses its involvement in the pathology of muscular dystrophies. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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22 pages, 1320 KiB

Open AccessReview

PPARs and Microbiota in Skeletal Muscle Health and Wasting

by Ravikumar Manickam, Kalina Duszka and Walter Wahli

Int. J. Mol. Sci. 2020, 21(21), 8056; https://doi.org/10.3390/ijms21218056 - 29 Oct 2020

Cited by 63 | Viewed by 7615

Abstract

Skeletal muscle is a major metabolic organ that uses mostly glucose and lipids for energy production and has the capacity to remodel itself in response to exercise and fasting. Skeletal muscle wasting occurs in many diseases and during aging. Muscle wasting is often [...] Read more.

Skeletal muscle is a major metabolic organ that uses mostly glucose and lipids for energy production and has the capacity to remodel itself in response to exercise and fasting. Skeletal muscle wasting occurs in many diseases and during aging. Muscle wasting is often accompanied by chronic low-grade inflammation associated to inter- and intra-muscular fat deposition. During aging, muscle wasting is advanced due to increased movement disorders, as a result of restricted physical exercise, frailty, and the pain associated with arthritis. Muscle atrophy is characterized by increased protein degradation, where the ubiquitin-proteasomal and autophagy-lysosomal pathways, atrogenes, and growth factor signaling all play an important role. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of transcription factors, which are activated by fatty acids and their derivatives. PPARs regulate genes that are involved in development, metabolism, inflammation, and many cellular processes in different organs. PPARs are also expressed in muscle and exert pleiotropic specialized responses upon activation by their ligands. There are three PPAR isotypes, viz., PPARα, -β/δ, and -γ. The expression of PPARα is high in tissues with effective fatty acid catabolism, including skeletal muscle. PPARβ/δ is expressed more ubiquitously and is the predominant isotype in skeletal muscle. It is involved in energy metabolism, mitochondrial biogenesis, and fiber-type switching. The expression of PPARγ is high in adipocytes, but it is also implicated in lipid deposition in muscle and other organs. Collectively, all three PPAR isotypes have a major impact on muscle homeostasis either directly or indirectly. Furthermore, reciprocal interactions have been found between PPARs and the gut microbiota along the gut–muscle axis in both health and disease. Herein, we review functions of PPARs in skeletal muscle and their interaction with the gut microbiota in the context of muscle wasting. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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34 pages, 1408 KiB

Open AccessReview

Skeletal Muscle Recovery from Disuse Atrophy: Protein Turnover Signaling and Strategies for Accelerating Muscle Regrowth

by Timur M. Mirzoev

Int. J. Mol. Sci. 2020, 21(21), 7940; https://doi.org/10.3390/ijms21217940 - 26 Oct 2020

Cited by 34 | Viewed by 6542

Abstract

Skeletal muscle fibers have a unique capacity to adjust their metabolism and phenotype in response to alternations in mechanical loading. Indeed, chronic mechanical loading leads to an increase in skeletal muscle mass, while prolonged mechanical unloading results in a significant decrease in muscle [...] Read more.

Skeletal muscle fibers have a unique capacity to adjust their metabolism and phenotype in response to alternations in mechanical loading. Indeed, chronic mechanical loading leads to an increase in skeletal muscle mass, while prolonged mechanical unloading results in a significant decrease in muscle mass (muscle atrophy). The maintenance of skeletal muscle mass is dependent on the balance between rates of muscle protein synthesis and breakdown. While molecular mechanisms regulating protein synthesis during mechanical unloading have been relatively well studied, signaling events implicated in protein turnover during skeletal muscle recovery from unloading are poorly defined. A better understanding of the molecular events that underpin muscle mass recovery following disuse-induced atrophy is of significant importance for both clinical and space medicine. This review focuses on the molecular mechanisms that may be involved in the activation of protein synthesis and subsequent restoration of muscle mass after a period of mechanical unloading. In addition, the efficiency of strategies proposed to improve muscle protein gain during recovery is also discussed. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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30 pages, 1235 KiB

Open AccessReview

Intensive Care Unit-Acquired Weakness: Not Just Another Muscle Atrophying Condition

by Heta Lad, Tyler M. Saumur, Margaret S. Herridge, Claudia C. dos Santos, Sunita Mathur, Jane Batt and Penney M. Gilbert

Int. J. Mol. Sci. 2020, 21(21), 7840; https://doi.org/10.3390/ijms21217840 - 22 Oct 2020

Cited by 65 | Viewed by 17703

Abstract

Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein [...] Read more.

Intensive care unit-acquired weakness (ICUAW) occurs in critically ill patients stemming from the critical illness itself, and results in sustained disability long after the ICU stay. Weakness can be attributed to muscle wasting, impaired contractility, neuropathy, and major pathways associated with muscle protein degradation such as the ubiquitin proteasome system and dysregulated autophagy. Furthermore, it is characterized by the preferential loss of myosin, a distinct feature of the condition. While many risk factors for ICUAW have been identified, effective interventions to offset these changes remain elusive. In addition, our understanding of the mechanisms underlying the long-term, sustained weakness observed in a subset of patients after discharge is minimal. Herein, we discuss the various proposed pathways involved in the pathophysiology of ICUAW, with a focus on the mechanisms underpinning skeletal muscle wasting and impaired contractility, and the animal models used to study them. Furthermore, we will explore the contributions of inflammation, steroid use, and paralysis to the development of ICUAW and how it pertains to those with the corona virus disease of 2019 (COVID-19). We then elaborate on interventions tested as a means to offset these decrements in muscle function that occur as a result of critical illness, and we propose new strategies to explore the molecular mechanisms of ICUAW, including serum-related biomarkers and 3D human skeletal muscle culture models. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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39 pages, 4136 KiB

Open AccessReview

MuRF1/TRIM63, Master Regulator of Muscle Mass

by Dulce Peris-Moreno, Daniel Taillandier and Cécile Polge

Int. J. Mol. Sci. 2020, 21(18), 6663; https://doi.org/10.3390/ijms21186663 - 11 Sep 2020

Cited by 73 | Viewed by 8908

Abstract

The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is [...] Read more.

The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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31 pages, 3550 KiB

Open AccessReview

How Postural Muscle Senses Disuse? Early Signs and Signals

by Boris S. Shenkman

Int. J. Mol. Sci. 2020, 21(14), 5037; https://doi.org/10.3390/ijms21145037 - 16 Jul 2020

Cited by 25 | Viewed by 3680

Abstract

A mammalian soleus muscle along with other “axial” muscles ensures the stability of the body under the Earth’s gravity. In rat experiments with hindlimb suspension, zero-gravity parabolic flights as well as in human dry immersion studies, a dramatic decrease in the electromyographic (EMG) [...] Read more.

A mammalian soleus muscle along with other “axial” muscles ensures the stability of the body under the Earth’s gravity. In rat experiments with hindlimb suspension, zero-gravity parabolic flights as well as in human dry immersion studies, a dramatic decrease in the electromyographic (EMG) activity of the soleus muscle has been repeatedly shown. Most of the motor units of the soleus muscle convert from a state of activity to a state of rest which is longer than under natural conditions. And the state of rest gradually converts to the state of disuse. This review addresses a number of metabolic events that characterize the earliest stage of the cessation of the soleus muscle contractile activity. One to three days of mechanical unloading are accompanied by energy-dependent dephosphorylation of AMPK, accumulation of the reactive oxygen species, as well as accumulation of resting myoplasmic calcium. In this transition period, a rapid rearrangement of the various signaling pathways occurs, which, primarily, results in a decrease in the rate of protein synthesis (primarily via inhibition of ribosomal biogenesis and activation of endogenous inhibitors of mRNA translation, such as GSK3β) and an increase in proteolysis (via upregulation of muscle-specific E3-ubiquitin ligases). Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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32 pages, 1287 KiB

Open AccessReview

Signaling Pathways That Control Muscle Mass

by Anna Vainshtein and Marco Sandri

Int. J. Mol. Sci. 2020, 21(13), 4759; https://doi.org/10.3390/ijms21134759 - 4 Jul 2020

Cited by 120 | Viewed by 17306

Abstract

The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as [...] Read more.

The loss of skeletal muscle mass under a wide range of acute and chronic maladies is associated with poor prognosis, reduced quality of life, and increased mortality. Decades of research indicate the importance of skeletal muscle for whole body metabolism, glucose homeostasis, as well as overall health and wellbeing. This tissue’s remarkable ability to rapidly and effectively adapt to changing environmental cues is a double-edged sword. Physiological adaptations that are beneficial throughout life become maladaptive during atrophic conditions. The atrophic program can be activated by mechanical, oxidative, and energetic distress, and is influenced by the availability of nutrients, growth factors, and cytokines. Largely governed by a transcription-dependent mechanism, this program impinges on multiple protein networks including various organelles as well as biosynthetic and quality control systems. Although modulating muscle function to prevent and treat disease is an enticing concept that has intrigued research teams for decades, a lack of thorough understanding of the molecular mechanisms and signaling pathways that control muscle mass, in addition to poor transferability of findings from rodents to humans, has obstructed efforts to develop effective treatments. Here, we review the progress made in unraveling the molecular mechanisms responsible for the regulation of muscle mass, as this continues to be an intensive area of research. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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18 pages, 4374 KiB

Open AccessReview

Emerging Strategies Targeting Catabolic Muscle Stress Relief

by Mattia Scalabrin, Volker Adams, Siegfried Labeit and T. Scott Bowen

Int. J. Mol. Sci. 2020, 21(13), 4681; https://doi.org/10.3390/ijms21134681 - 30 Jun 2020

Cited by 11 | Viewed by 5394

Abstract

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven [...] Read more.

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitors, myostatin antibodies, β₂ adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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19 pages, 1896 KiB

Open AccessReview

Progressive Skeletal Muscle Atrophy in Muscular Dystrophies: A Role for Toll-Like Receptor-Signaling in Disease Pathogenesis

by Boel De Paepe

Int. J. Mol. Sci. 2020, 21(12), 4440; https://doi.org/10.3390/ijms21124440 - 22 Jun 2020

Cited by 24 | Viewed by 5166

Abstract

Muscle atrophy is an active process controlled by specific transcriptional programs, in which muscle mass is lost by increased protein degradation and/or decreased protein synthesis. This review explores the involvement of Toll-like receptors (TLRs) in the muscle atrophy as it is observed in [...] Read more.

Muscle atrophy is an active process controlled by specific transcriptional programs, in which muscle mass is lost by increased protein degradation and/or decreased protein synthesis. This review explores the involvement of Toll-like receptors (TLRs) in the muscle atrophy as it is observed in muscular dystrophies, disorders characterized by successive bouts of muscle fiber degeneration and regeneration in an attempt to repair contraction-induced damage. TLRs are defense receptors that detect infection and recognize self-molecules released from damaged cells. In muscular dystrophies, these receptors become over-active, and are firmly involved in the sustained chronic inflammation exhibited by the muscle tissue, via their induction of pro-inflammatory cytokine expression. Taming the exaggerated activation of TLR2/4 and TLR7/8/9, and their downstream effectors in particular, comes forward as a therapeutic strategy with potential to slow down disease progression. Full article

(This article belongs to the Special Issue Muscle Atrophy: Discovery of Mechanisms and Potential Therapies)

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